The synthesis and secretion of the major secretory proteins of the pancreas is episodically regulated to meet rapidly changing physiological and developmental needs of the organism. Mobilization of calcium fromendoplasmic reticulum (ER) stores mediates exocytosis from secretory granules. Although the mechanisms of stimulus-coupled secretion in the pancreas are well understood, relatively little is known about the regulation of the genes that control pancreatic secretory capacity and the maintenance of the differentiated state. Mice ablated for the PERK eIF2alpha kinase gene display exocrine pancreatic defects that include reduced digestive enzyme production, transdifferentiation to liver-like cells and degeneration of pancreatic structure that is accompanied by proliferation of fibroblasts that invade the acini. PERK-dependent endocrine defects are characterized by the early neonatal loss of islet beta cells, which ultimately leads to an almost complete disappearance of the islets and loss of glycemic control by the third postnatal week. We show that the progressive loss of the islets during the neonatal period in Perk-/- mice is due to a failure of the 13cells to proliferate and not the result of an increase in beta cell apoptosis. The loss of PERK function is also associated with early infantile pancreatic failure in humans with the Wolcott-Rallison Syndrome. We propose that the physiological regulation of PERK activity mediates beta cell proliferation factors and regulates other genes that control the secretory capacity and differentiated state of the pancreas. The major focus of this proposal is to determine the regulatory and metabolic pathways that are controlled by PERK. Using a genetic approach we will determine the cellular basis for PERK-dependent maintenance of beta cell mass that includes approaches to identify potential 13cell proliferation factors that are regulated by PERK. We will also assess the importance of PERK for the normal pancreatic development and will determine if PERK regulates the expression of genes that function to modulate the secretory capacity of both the endocrine and exocrine pancreas. Our studies will directly bear on the pathophysiology of Wolcott-Rallison syndrome, and in particular the early onset of diabetes mellitus.